Primary immune deficiency diseases provide an unparalleled resource for investigators in human immunology. Although the first primary immune deficiencies were described in infants with severe disease, primary immune defects are found in humans of all ages, leading to characteristic complications and significant mortality. While there have been amazing advances in the understanding many conditions, the more prevalent immune defects which impair B cell function, common variable immune deficiency, IgA deficiency, IgG subclass and specific antibody deficiency, are still largely uncharted territory. In this program we focus on a group of interlocking themes, including the biology of transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and the function of its ligands and toll like receptor ligands (TLR) in B cell differentiation and maturation. Engagement of TACI by its ligands B cell activating factor (BAFF) or a proliferation inducing ligand (APRIL) up-regulate the expression of activation-induced cytidine deaminase (AID), a DNA-editing enzyme essential for both class switch recombination (CSR) and somatic hypermutation (SHM.) These ligands, together with microbial agonists of Toll-like receptors (TLR) can also induce Ig CSR and perhaps even SHM in human B cells. Our data show that both TACI and TLR pathways are essential for the elimination of autoimmune B cells and the development of tolerance in humans. Aside from these pathways, the genetic factors that promote anti-bacterial immunity in humans are largely unknown, thus we have also undertaken a genome-wide approach, investigating patients with no known genetic defect who have experienced severe pneumococcal disease due to impaired Ab response to glycans. These approaches have already defined new primary immune defects and will add an entirely new dimension to the study of B cell defects. These new discoveries made using human tissues clearly promise further advances in understanding human B cell biology. This group of investigators has been drawn together by shared synergy, enthusiasm and passion for this field. Our established collaborations, with a proven track record of ongoing accomplishments, demonstrate the success of this approach. RELEVANCE (See instructions): Defects of the humoral immune system lead to infectious diseases, an inability to be vaccinated, immune dysregulation and autoimmune disease. In this Program Project, we will investigate a group of related human B cell defects, using coordinated genetic and molecular techniques to define these pathological processes. Project 1 - Investigating Blocks to B Cell Memory in CVID (Project Leader: Cunningham-Rundles, C.) Description as provided by applicant: Common variable immune deficiency (CVID) is the clinically most important primary antibody deficiency disease due to prevalence, complications, hospitalizations and requirement for lifelong immune globulin therapy. B cells of patients lack the capacity for normal somatic hyper-mutation and isotype switch, secrete immune globulins poorly, and fail to differentiate into plasma cells. The genetic causes of B cell dysfunction in CVID are largely unknown. Heterozygous mutations in the transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) gene are found in 8-10%, but also in relatives with normal immune globulin levels showing that these are not the main cause of severe B cell dysfunction. However, CVID subjects with TACI mutation especially in heterozygous form are significantly more likely to develop striking lymphoid hyperplasia and autoimmunity. Using human B cells and transfectants with TACI mutations, we will investigate TACI receptor function in humans, examining if monoallellic or biallelic mutations in TACI accelerate BAFF/BAFF-R mediated B cell growth and differentiation. TLR agonists with TACI signals may promote self-reactivity as well as play a role in B cell differentiation in humans, thus we will examine how these may drive B cell proliferation and autoimmunity in CVID, especially when TACI signals are impaired. As human B cells have two structurally different TACI isoforms we will determine the differences in functional capacities, and explore the controls on the production of these naturally occurring isoforms. A current hypothesis is that mutations in TACI could lead to haplo insufficiency;we will investigate this by examining B cell function in patients with the Smith Magenis syndrome, who are heterozygous for a null TACI allele due to a chromosomal deletion. In this project we hypothesize that mutations in TACI found in subjects with CVID and their non immune deficient relatives, can be used to explore how the TACI receptor and its ligands, BAFF and APRIL, control B cell growth and differentiation in humans. These data may be of use in understanding this complex receptor system in human autoimmune disease in general. RELEVANCE: 8-10% of patients CVID have mutations in the gene encoding TACI, a poorly understood B cell receptor that exerts controls on B cell immunity while playing a role in antibody production to carbohydrate antigens. We hypothesize that mutations in this receptor and its isoforms can be used to elucidate the complex functions of this receptor in a human system.